Neutrophil elastase is a broad spectrum protease that is known to have access to the tissues of the lung. This protease is generally capable of degrading all major protein components of the alveolar interstitium. The unrestrained action of this protease, with its elastolytic properties can lead to the destruction of lung connective tissue and to the anatomic and functional derangements of pulmonary emphysema. Smith, et al., J. Clin. Invest. 84:1145-1154 (1989).
.alpha.1-antitrypsin (".alpha.1AT") is a protease inhibitor with inhibitory activity toward neutrophil elastase. A deficiency of .alpha.1-antitrypsin in the lower respiratory tract has been found to be central to the pathogenesis of emphysema due to the critical role of .alpha.1AT in protecting alveolar structures from neutrophil elastase. .alpha.1AT deficiency is a genetic disorder characterized by low plasma and lung levels of the inhibitor and the development of emphysema by the third to fourth decades.
In addition to genetic deficiencies in .alpha.1AT, it has been found that the lungs of cigarette smokers are burdened with neutrophils. In particular, significantly increased numbers of neutrophils have been found in cell suspensions isolated from bronchoalveolar lavage fluid and from open lung biopsies of both normal and sarcoid cigarette smokers compared with non-smokers. Hunnighake and Crystal, Am. Rev. Respir. Dis. 128:833-838 (1983).
Treatment methods for .alpha.1AT deficiency, whether genetic or acquired, have primarily focused around augmentation therapy, providing an exogenous source of .alpha.1AT to patients suffering from such a deficiency. Intravenous administration has been previously employed in this augmentation therapy to provide an exogenous source of .alpha.1AT. However, in order to provide effective concentrations of the inhibitor in the tissue where it is needed, e.g., lung tissue, intravenous methods require administration of large amounts of .alpha.1AT, e.g., 4 to 5 grams/week. Further, this intravenous administration generally must be carried out in a hospital setting.
Successful results have been reported using aerosol administration of liquid .alpha.1AT formulations. Aerosol administration provides local delivery of the inhibitor to the effected tissue of the lower respiratory tract, thereby requiring lower dosages. See, Published European Patent Application No. 0 289 336, Smith et al., J. Clin. Invest. 84:1145-1154 (1989), Hubbard et al. J. Clin. Invest. 84:1349-1354 (1989), Hubbard, et al. Lung Suppl. 565-578 (1990).
Despite the improvements in .alpha.1AT augmentation therapy, problems still remain. In particular, previously reported liquid aerosol methods provide effective levels of .alpha.1AT in the lung tissue for only short periods, e.g., on the order of several hours, thereby requiring often repeated treatments at higher dosage levels, e.g., &gt;200 mg/day. Thus, there is need for a method of administering .alpha.1AT to patients which will provide longer term benefits from a single treatment, thereby requiring lower and fewer doses. The present invention meets these and other needs.